Methylphenidate (MPH, methyl 2-phenyl-2-(piperidin-2-yl)acetate, a 5HT1A receptor agonist) is sold under the trademarks RITALIN, CONCERTA®, APTENSIO, BIPHENTIN, DAYTRANA, EQUASYM, MEDIKINET, METADATE, METHYLIN, QUILLIVANT and others. It is commonly used for the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and for off-label use in the treatment of postural orthostatic tachycardia syndrome, lethargy, fatigue, bipolar disorder, lack of attention (lack of attentiveness), opioid induced somnolence, major depressive disorder and obesity. It has a plasma half-life of about 2-3 hours, so immediate or rapid release dosage forms are typically administered two to four times daily. Common dosage forms include conventional tablets, capsules, chewable tablets and oral solutions, which are indicated as needing to be administered 30-45 min before a meal. MPH can be administered alone or can be administered as adjunct therapy.
There is the possibility of developing dependence upon MPH (a Schedule II drug), especially if it is abused. Consuming alcohol (ethanol or a beverage containing ethanol) is one way to enhance the bioavailability of MPH by up to 40% (Patrick et al., “Influence of ethanol and gender on methylphenidate pharmacokinetics and pharmacodynamics” in Clin. Pharm. Thera. (March 2007), 81(3), 346-353). Too rapid of a release of MPH will result in too high of a Cmax, too short of a Tmax, increased adverse events and increased release of dopamine, which results in a euphoric effect and thus leads to abuse and addiction. In fact, ethylphenidate can be formed in vivo after ingestion of ethanol and MPH (Markowitz et al., “Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion”, in J. Clin. Psychopharm. (1999), 19(4), 362-366). There is a need to provide extended release dosage forms that are resistant to such alcohol ingestion-related dose dumping.
In view of the short half-life of MPH, extended release tablet, capsule, powder, particle and osmotic device dosage forms have been developed: METADATE-ER, RITALIN-SR, APTENSIO-XR, METADATE-CD, RITALIN-LA, CONCERTA®, QUILLIVANT-XR. Even transdermal dosage forms are available. Extended release dosage forms include higher doses of MPH and, so, are useful for reducing the total number of daily doses required. Extended release dosage forms containing MPH have been suggested by or disclosed in the patent literature: U.S. Pat. No. 4,285,987, U.S. Pat. No. 4,200,098, U.S. Pat. No. 5,558,879, U.S. Pat. No. 4,449,983, U.S. Pat. No. 4,576,604, U.S. Pat. No. 4,673,405, U.S. Pat. No. 5,593,694, U.S. Pat. No. 3,625,214, U.S. Pat. No. 4,814,181, U.S. Pat. No. 5,474,786, U.S. Pat. No. 4,892,778, U.S. Pat. No. 4,940,465, U.S. Pat. No. 4,915,954, U.S. Pat. No. 4,874,388, U.S. Pat. No. 4,957,494, U.S. Pat. No. 5,156,850, U.S. Pat. No. 5,232,705, U.S. Pat. No. 5,785,994, U.S. Pat. No. 4,612,008, U.S. Pat. No. 5,178,866, U.S. Pat. No. 4,142,526, U.S. Pat. No. 4,036,227, U.S. Pat. No. 9,144,549, U.S. Pat. No. 8,629,179, U.S. Pat. No. 8,163,798, U.S. Pat. No. 6,930,129, U.S. Pat. No. 6,919,373.
Literature reports, however, that some oral extended release dosage forms may exhibit dose dumping when coadministered orally with an alcoholic beverage (Meisner et al. “Extended release stimulant medication misuse with alcohol co-administration”, in J. Can. Acad. Child Adolesc. Psychiatry (November 2008), 17(4), 181-182). For example, literature reports that extended release capsules but not CONCERTA®, an OROS® osmotic device with a tri-layered core, exhibit dose dumping in vitro when placed in alcoholic solution. 98 or 84% of the drug was released from RITALIN LA (40-mg) or METADATE CD (60-mg) capsules within the first hour at an alcohol concentration of 40% (UCB, Inc. METADATE CD once-daily MPH HCl extended-release capsules prescribing information, Smyrna, G A, 2015 February; Novartis, RITALIN LA MPH HCl extended-release capsules prescribing information, East Hanover, N J, 2015 July). 96% was released from APTENSIO XR (80-mg) capsules within 2 hours at an alcohol concentration up to 40% (Rhodes Pharmaceuticals, APTENSIO XR MPH HCl extended-release capsules prescribing information, Coventry, R I, 2015 April; Janssen Pharmaceuticals, Inc. CONCERTA® MPH HCl extended-release tablets prescribing information, Titusville, N.J.; 2015 April).
The product insert for CONCERTA® osmotic devices, which provide an ascending release rate for MPH over a period of at least 5-6 h, includes a comparative summary of the pharmacokinetic parameters for a single 18 mg dose of CONCERTA® once daily versus a 5 mg dose of rapid release tablet three times daily.
CONCERTA ®MPHParameter18 mg 1x daily5 mg 3x dailyCmax (ng/mL)3.7 ± 1.04.2 ± 1.0Tmax (h)6.8 ± 1.86.5 ± 1.8AUCinf (ng-g/mL)41.8 ± 13.938.0 ± 11.0T½ (h)3.5 ± 0.43.0 ± 0.5
The comparative plasma profiles are depicted in FIG. 1. The product literature also reports no food effect and no food-related dose-dumping.
Even though the literature asserts that oral ingestion of alcohol results in no alcohol-related dose-dumping effect upon release of MPH from CONCERTA® osmotic devices, the present inventors have found substantial evidence to the contrary. It would be a significant addition to the art to provide a controlled release dosage form suitable for once or twice daily oral administration that still provides therapeutic levels of MPH for an extended period of time while concomitantly reducing the potential for dose-dumping caused by ethanol.
There are other dosage form known to exhibit alcohol-related dose-dumping. Such dosage forms typically contain a narcotic (stimulant) or other abusable drug as the therapeutic agent or active ingredient. It would be a significant advancement in the art to provide a controlled release dosage form suitable for once or twice daily oral administration that provides therapeutic levels of the narcotic for an extended period of time while concomitantly reducing the potential for dose-dumping caused by ethanol.